side of the tablet can be applied. tablet should be applied on the same side of the mouth as the herpes labialis symptoms. once applied, sitavig stays in position and gradually dissolves during the day. [see clinical pharmacology (12.3) ]. in addition, sitavig should not be crushed, chewed, sucked or swallowed. food and drink can be taken normally when sitavig is in place. avoid any situations which may interfere with adhesion of the tablet such as chewing gum, touching or pressing the tablet after placement, wearing upper dentures, and brushing teeth. if the teeth need to be cleaned while the tablet is in place, rinse the mouth gently. drink plenty of liquids in the case of dry mouth. if sitavig does not adhere or falls off within the first 6 hours , the same tablet should be repositioned immediately. if the tablet cannot be repositioned, a new tablet should be placed. if sitavig is swallowed within the first 6 hours , the patient should drink a glass of water and a new tablet should be applied. [see patient counseling information (17) ]. sitavig does not need to be reapplied if the tablet falls out or is swallowed after the first 6 hours.

f patients can be seen in table 1. table 1: selected treatment emergent adverse events reported in at least 1% of patients event sitavig n = 378 placebo n = 397 nervous system disorders headache 3% 3% dizziness 1% 1% lethargy 1% 0 gastrointestinal system disorders gingival pain 1% 0.3% aphthous stomatitis 1% 0 administration site conditions application site pain 1% 1% application site irritation 1% 0 skin and subcutaneous disorders erythema 1% 0.3% rash 1% 0.3% the treatment emergent adverse events considered related to treatment that occurred in greater than or equal to 1% of patients included headache (1% sitavig vs. 2% placebo) and application site pain (1% both arms). there was no discontinuation of sitavig due to adverse drug reactions. most treatment related adverse events were mild or moderate in severity. one report of headache from both treatment arms was classified as severe.

efits of breastfeeding should be considered along with the mother's clinical need for sitavig and any potential adverse effects on the breastfed child from sitavig or from the underlying maternal condition. 8.4 pediatric use safety and effectiveness of sitavig in pediatric patients have not been established. the ability of pediatric patients to comply with the application instructions has not been evaluated. use in younger children is not recommended due to potential risk of choking. 8.5 geriatric use clinical studies of sitavig did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. 8.6 immunocompromised patients the safety of sitavig has not been studied in immunocompromised subjects.

05) 12 (5-16) in the phase 3 study, the levels of acyclovir in saliva were measured within 24 hours of sitavig application in 56 patients with recurrent herpes labialis (mean value 88.1 micrograms per ml) and were within the range of those observed in the pk study in healthy volunteers. in healthy volunteers, the median duration of buccal adhesion was 14 hours following application of a single sitavig 50 mg tablet. plasma plasma concentrations of acyclovir were measured in 12 healthy volunteers after a singledose application of sitavig 50 mg buccal tablet. acyclovir concentrations had a delayed appearance (undetectable at 5 hours) and were below the concentrations required for antiviral activity (range: 17.5 to 55.3 nanogram per ml). metabolism and excretion acyclovir is metabolized to 9-[(carboxymethoxy)methyl]guanine (cmmg) and 8-hydroxy-acyclovir (8-oh-acv) by oxidation and hydroxylation, and is primarily excreted unchanged by the kidneys. food effect there was no formal food effect study conducted with sitavig; however, in clinical studies patients were allowed to eat and drink while taking sitavig. 12.4 microbiology mechanism of action acyclovir is a synthetic purine deoxynucleoside analogue with inhibitory activity against herpes simplex viruses type 1 (hsv-1) and type 2 (hsv-2) dna polymerases. it inhibits hsv-1 and hsv-2 replication in cell culture and in vivo . the inhibitory activity of acyclovir is selective due to its affinity for the enzyme thymidine kinase encoded by hsv. this viral enzyme converts acyclovir into acyclovir monophosphate, a deoxynucleotide analogue. the monophosphate is further converted into diphosphate by cellular guanylate kinase and into triphosphate by a number of cellular enzymes. in biochemical assays, acyclovir triphosphate inhibits replication of α-herpes viral dna. this inhibition is accomplished in 3 ways: 1) competitive inhibition of viral dna polymerase, 2) incorporation into and termination of the growing viral dna chain, and 3) inactivation of the viral dna polymerase. antiviral activity the quantitative relationship between the susceptibility of herpes viruses to antivirals in cell culture and the clinical response to therapy has not been established in humans, and virus sensitivity testing has not been standardized. sensitivity testing results, expressed as the concentration of drug required to inhibit by 50% the growth of virus in cell culture (ec 50 ), vary greatly depending upon a number of factors. using plaque-reduction assays on vero cells, the ec 50 values of acyclovir against herpes virus isolates ranged from 0.09 to 60 µm (0.02 to 13.5 µg/ml) for hsv-1 and from 0.04 to 44 µm (0.01 to 9.9 μg/ml) for hsv-2. resistance in cell culture acyclovir-resistant hsv-1 and hsv-2 strains were isolated in cell culture. acyclovirresistant hsv resulted from mutations in the viral thymidine kinase (tk; pul23) and dna polymerase (pol; pul30) genes. frameshifts were commonly isolated and result in premature truncation of the hsv tk product with consequent decreased susceptibility to acyclovir. mutations in the viral tk gene may lead to complete loss of tk activity (tk negative), reduced levels of tk activity (tk partial), or alteration in the ability of viral tk to phosphorylate the drug without an equivalent loss in the ability to phosphorylate thymidine (tk altered). in cell culture the following resistance-associated substitutions in tk of hsv-1 and hsv-2 were observed (table 3). table 3: summary of acyclovir (acv) resistance-associated amino acid substitutions in cell culture hsv-1 tk p5a, h7q, l50v, g56v, g59a, g61a, k62n, t63a, e83k, p84s, d116n, p131s, r163h, a167v, p173l, q185r, r216s, r220h, t245m, r281stop, t287m, m322k hsv-2 tk l69p, c172r, t288m hsv-1 pol d368a, y557s, e597d, v621s, l702h, n815s, v817m,g841c hsv-2 pol - in hsv-infected patients clinical hsv-1 and hsv-2 isolates obtained from patients who failed treatment for their α-herpesvirus infections were evaluated for genotypic changes in the tk and pol genes and for phenotypic resistance to acyclovir (table 4). hsv isolates with frameshift mutations and resistance-associated substitutions in tk and pol were identified. the listing of substitutions in the hsv tk and pol leading to decreased susceptibility to acyclovir is not all inclusive and additional changes will likely be identified in hsv variants isolated from patients who fail acyclovir-containing regimens. the possibility of viral resistance to acyclovir should be considered in patients who fail to respond or experience recurrent viral shedding during therapy. table 4: summary of acv resistance-associated amino acid substitutions observed in treated patients note: many additional pathways to acyclovir resistance likely exist. hsv-1 tk g6c, r32h, r41h, r51w, y53c/d/h, y53stop, d55n, g56d/s, p57h, h58n/r/y, g59r, g61a, k62n, t63i, q67stop, s74stop, y80n, e83k, p84l, y87h, w88r, r89q/w, e95stop, t103p, q104h, q104stop, h105p, d116n, m121l/r, s123r, q125h, m128l, g129d, i143v, a156v, d162a/h/n, r163g/h, l170p, y172c, p173l, a174p, a175v, r176q/w, r176stop, l178r, s181n, v187m, a189v, v192a, g200c/d/s, t201p, v204g, a207p, l208f/h, r216c/h, r220c/h, r221h, r222c/h, l227f, t245m/p, l249p, q250stop, c251g, r256w, e257k, q261r, t287m, l288stop, l291p/r, l297s, l315s, l327r, c336y, q342stop, t354p, l364p, a365t hsv-2 tk r34c, g39e, r51w, y53n, g59p, g61w, s66p, a72s, d78n, p85s, a94v, n100h, i101s, q105p, t131p, d137stop, f140l, l158p, s169p, r177w, s182n, m183i, v192m, g201d, r217h, r221c/h, q222stop, r223h, y239stop, r271v, p272s, d273r, t287m, c337y hsv-1 pol k532t, q570r, l583v, a605v, a657t, d672n, v715g, a719t/v, s724n, f733c, e771q, s775n, l778m, e798k, v813m, n815s, g841s, i890m, g901v, v958l, h1228d hsv-2 pol e250q, d307n, k533e, a606v, c625r, r628c, e678g, a724v, s725g, s729n, i731f, q732r, m789k/t, v818a, n820s, y823c, q829r, t843a, m910t, d912n/v, a915v, f923l, t934a, r964h cross-resistance cross-resistance has been observed among hsv isolates carrying frameshift mutations and resistance-associated substitutions, which confer reduced susceptibility to penciclovir (pcv), famciclovir (fcv), and foscarnet (fos) [table 5]. table 5: summary of amino acid substitutions conferring cross-resistance to pcv, fcv or fos cross-resistant to pcv/fcv hsv-1 tk g6c, r32h, r51w, y53c/h, h58n, g61a, s74stop, e83k, p84l, t103p, q104stop, d116n, m121r, i143v, r163h, l170p, y172c, a174p, r176q/w, q185r, a189v, g200d, l208h, r216c, r220h, r222c/h, t245m, q250stop, r256w, r281stop, t287m, l315s, m322k, c336y cross-resistant to pcv/fcv hsv-1 pol a657t, d672n, v715g, a719v, s724n, e798k, n815s, g841s cross-resistant to pcv/fcv hsv-2 tk g39e, r51w, y53n, r177w, r221h, t288m cross-resistant to pcv/fcv hsv-2 pol k533e, a606v, c625r, r628c, s729n, q732r, m789k/t, v818a, n820s, f923l, t934a cross-resistant to fos hsv-1 pol d368a, a605v, d672n, l702h, v715g, a719t/v, s724n, l778m, e798k, v813m, n815s, v817m, g841c/s, i890m cross-resistant to fos hsv-2 pol k533e, a606v, c625r, r628c, a724v, s725g, s729n, i731f, q732r, m789k/t, v818a, y823c d912v, f923l, t934a, r964h

ecurrent herpes labialis (mean value 88.1 micrograms per ml) and were within the range of those observed in the pk study in healthy volunteers. in healthy volunteers, the median duration of buccal adhesion was 14 hours following application of a single sitavig 50 mg tablet. plasma plasma concentrations of acyclovir were measured in 12 healthy volunteers after a singledose application of sitavig 50 mg buccal tablet. acyclovir concentrations had a delayed appearance (undetectable at 5 hours) and were below the concentrations required for antiviral activity (range: 17.5 to 55.3 nanogram per ml). metabolism and excretion acyclovir is metabolized to 9-[(carboxymethoxy)methyl]guanine (cmmg) and 8-hydroxy-acyclovir (8-oh-acv) by oxidation and hydroxylation, and is primarily excreted unchanged by the kidneys. food effect there was no formal food effect study conducted with sitavig; however, in clinical studies patients were allowed to eat and drink while taking sitavig.

ions by applying the tablet to the buccal mucosa in the canine fossa. if the tablet was detached within the first 6 hours, subjects were instructed to reapply a tablet. the mean and median durations of the recurrent herpes labialis episode (itt population, n=771) were approximately half a day shorter in patients treated with sitavig compared with patients treated with placebo.

out or you swallow it after it has been in place 6 hours or longer. if you swallow sitavig within the first 6 hours of applying it, drink a glass of water and place a new sitavig tablet onto your upper gum. 17.2 adverse reactions patients may experience adverse reactions including headache, and application site pain.

thcare provider about all the medicines you take, including prescription or over-the-counter medicines, vitamins, and herbal supplements. how should i use sitavig? see the detailed instructions for use for information about how to use sitavig. use sitavig exactly as your healthcare provider tells you to use it. use sitavig within 1 hour after you have the first symptom of a cold sore, such as itching, redness, burning, or tingling, and before a cold sore appears. you may eat and drink while using sitavig. do not crush, chew, suck, or swallow sitavig tablets. sitavig will slowly dissolve over time while in your mouth and should be left in place. gently rinse your mouth with water to clean your teeth while sitavig is in place. drink more liquids if your mouth becomes dry while using sitavig. what should i avoid while using sitavig? you should avoid activities that may prevent sitavig from sticking to your gum, including: touching or pressing sitavig after you apply it, wearing upper dentures, chewing gum, and brushing your teeth during the treatment day. what are the possible side effects of sitavig? the most common side effects of sitavig include: headache and pain where sitavig is applied. these are not all the possible side effects of sitavig. call your doctor for medical advice about side effects. you may report side effects to fda at 1-800-fda-1088. how should i store sitavig? store sitavig between 68°f to 77°f (20°c to 25°c). keep sitavig tablets dry. keep sitavig and all medicines out of the reach of children. general information about the safe and effective use of sitavig medicines are sometimes prescribed for purposes other than those listed in a patient information leaflet. do not use sitavig for a condition for which it was not prescribed. do not give sitavig to other people, even if they have the same symptoms that you have. it may harm them. you can ask your pharmacist or healthcare provider for information about sitavig that is written for health professionals. what are the ingredients in sitavig? active ingredient: acyclovir inactive ingredients: hypromellose, milk protein concentrate, sodium lauryl sulfate, magnesium stearate, microcrystalline cellulose, povidone, colloidal silicon dioxide. manufactured by: farméa, 10 rue bouché thomas, zac d'orgemont, 49 000 angers - france for more information call 1-800-499-4468.